Protein Kinase C α and β compensate for each other to promote stem cell factor-mediated KIT phosphorylation, mast cell viability and proliferation
Mast cells (MCs) develop from hematopoietic progenitors and differentiate into mature MCs that reside within connective or mucosal tissues. Though the number of MCs in tissues usually remains constant, inflammation and asthma disturb this homeostasis, leading to proliferation of MCs. Understanding the signaling events behind this proliferative response could lead to the development of novel strategies for better management of allergic diseases. MC survival, proliferation, differentiation, and migration are all maintained by a MC growth factor, stem cell factor (SCF) via its receptor, KIT. Here, we explored how protein kinase C (PKC) redundancy influences MC proliferation in bone marrow-derived MC (BMMC). We found that SCF activates PKCα and PKCβ isoforms, which in turn modulates KIT phosphorylation and internalization. Further, PKCα and PKCβ activate p38 mitogen activated protein kinase (MAPK), and this axis subsequently regulates SCF-induced MC cell proliferation. To ascertain the individual roles of PKCα and PKCβ, we knocked down either PKCα or PKCβ or both via short hairpin RNA (shRNA) and analyzed KIT phosphorylation, p38 MAPK phosphorylation, and MC viability and proliferation. To our surprise, downregulation of neither PKCα nor PKCβ affected MC viability and proliferation. In contrast, blocking both PKCα and PKCβ significantly attenuated SCF-induced cell viability and proliferation, suggesting that PKCα and PKCβ compensate for each other downstream of SCF signaling to enhance MC viability and proliferation. Our results not only suggest that PKC classical isoforms are novel therapeutic targets for SCF/MC-mediated inflammatory and allergic diseases, but they also emphasize the importance of inhibiting both PKCα and β isoforms simultaneously to prevent MC proliferation.
Lakshminarayan Reddy Teegala
Yasmine Elshoweikh
Ravindra Gudneppanavar
Sathwika Thodeti
Sabita Pokhrel
Erik Southard
Charles K Thodeti
Sailaja Paruchuri
FASEB J
. 2022 May;36(5):e22273. doi: 10.1096/fj.202101838RRR.
2022
English
Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration.
microglia; neuroprotection; Parkinson's disease; proliferation
Increased pro‐inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor‐1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF‐1, is increased in the brain of PD patients compared to controls. In two different neurotoxic mouse models of PD, acute MPTP and sub‐chronic LPS treatment, mRNA and protein levels of CSF1R and CSF‐1 were significantly increased. Treatment with the CSF1R inhibitor GW2580 significantly attenuated MPTP‐induced CSF1R activation and Iba1‐positive cell proliferation, without a reduction of the basal Iba1‐positive population in the substantia nigra. GW2580 treatment also significantly decreased mRNA levels of pro‐inflammatory factors, without alteration of anti‐inflammatory mediators, and significantly attenuated the MPTP‐induced loss of dopamine neurons and motor behavioral deficits. Importantly, these effects were observed in the absence of overt microglial depletion, suggesting that targeting CSF1R signaling may be a viable neuroprotective strategy in PD that disrupts pro‐inflammatory signaling, but maintains the beneficial effects of microglia. [ABSTRACT FROM AUTHOR]
Neal Matthew L; Fleming Sheila M; Budge Kevin M; Boyle Alexa M; Kim Chunki; Alam Gelareh; Beier Eric E; Wu Long‐Jun; Richardson Jason R
FASEB Journal
2020
2020-01
Journal Article
<a href="http://doi.org/10.1096/fj.201900567RR" target="_blank" rel="noreferrer noopener">10.1096/fj.201900567RR</a>
Differential Regulation Of Cysteinyl Leukotriene Receptor Signaling By Protein Kinase C In Human Mast Cells
activation; antagonist; asthmatic subjects; desensitization; expression; hyperresponsiveness; intestinal epithelial-cells; proliferation; pulmonary inflammation; responses; Science & Technology - Other Topics
Cysteinyl leukotrienes (cys-LTs) are a group of lipid mediators that are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness. Cys-LTs play an essential role in asthma and are synthesized as well as activated in mast cells (MCs). Cys-LTs relay their effects mainly through two known GPCRs, CysLT(1)R and CysLT(2)R. Although protein kinase C (PKC) isoforms are implicated in the regulation of CysLT(1)R function, neither the role of PKCs in cys-LT-dependent MC inflammatory signaling nor the involvement of specific isoforms in MC function are known. Here, we show that PKC inhibition augmented LTD4 and LTE4-induced calcium influx through CysLT(1)R in MCs. In contrast, inhibition of PKCs suppressed c-fos expression as well MIP1 beta generation by cys-LTs. Interestingly, cys-LTs activated both PKC alpha and PKC epsilon isoforms in MC. However, knockdown of PKC alpha augmented cys-LT mediated calcium flux, while knockdown of PKC epsilon attenuated cys-LT induced c-fos expression and MIP1 beta generation. Taken together, these results demonstrate for the first time that cys-LT signaling downstream of CysLT(1)R in MCs is differentially regulated by two distinct PKCs which modulate inflammatory signals that have significant pathobiologic implications in allergic reactions and asthma pathology.
Kondeti V; Duah E; Al-Azzam N; Thodeti C K; Boyce J A; Paruchuri S
Plos One
2013
2013-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1371/journal.pone.0071536" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0071536</a>
Experiments With Osteoblasts Cultured Under Varying Orientations With Respect To The Gravity Vector
attachment; averaged gravity; Biotechnology & Applied Microbiology; bone; Cell Biology; cell-culture; clinostat; gene-expression; growth; growth rate; in-vitro; inversion; microgravity; osteoblasts; proliferation; space; substrate
Substrate attachment is crucial for normal growth and differentiation of many cell types. To better understand the role of gravity in osteoblast attachment and growth in vitro, 17-day-old embryonic chick calvarial osteoblasts were subjected to directional variations with respect to gravity. Osteoblasts, grown in MEM or DME supplemented with 10% FBS and attached to type I collagen-coated coverslips, were loaded into cylindrical containers completely filled with medium and oriented so that cells were either atop or beneath, or coverslips continuously rotated (similar to2 rpm) in a clinostat, thereby continuously changing their orientation with respect to gravity. Cells in these three conditions were collected daily for up to 6 days, and cell viability, two osteoblast functions, and proliferation were assessed. Data suggest the number and function of attached osteoblasts is unaltered by inversion or clino-rotation in initially confluent cultures. In sparsely plated cultures, however, osteoblast viability was significantly decreased (similar to50%) in inverted and rotated cultures during the first 3 days of sampling, but from days 4 - 6 no significant difference was found in viable cell number for the three conditions. Decreases in viable cell number within the first days of the experiments could result from death followed by detachment, detachment followed by death, differences in proliferation rate, or lag-phase duration. To help distinguish among these, BrdU labeling for 2 or 24 hr was used to assess cell proliferation rate. Log-phase growth rates were calculated and were unchanged among the three conditions tested. These results point to an increase in lag-phase duration in inverted and rotated cultures. In summary, changing the cell-substrate attachment direction with respect to gravity causes an immediate response in the form of diminished viable osteoblast number in sparse, early cultures, but the effect disappears after 3 - 4 days and does not occur in mature, confluent cultures.
Kacena M A; Todd P; Gerstenfeld L C; Landis W J
Cytotechnology
2002
2002
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1023/a:1023936503105" target="_blank" rel="noreferrer noopener">10.1023/a:1023936503105</a>
Detecting Dna Synthesis Of Neointimal Formation After Catheter Balloon Injury In Gk And In Wistar Rats: Using 5-ethynyl-2 '-deoxyuridine
alkynes; arterial injury; balloon injury; Cardiovascular System & Cardiology; carotid-artery; Catheter; cell-cycle progression; click chemistry; diabetes-mellitus; diabetes-mellitus; DNA synthesis; EdU; eluting stents; Endocrinology & Metabolism; in-vitro; mammalian target; Neointimal formation; PCNA; proliferation; terminal
Background: Neointimal formation plays an important role in the pathogenesis of coronary restenosis after percutaneous coronary intervention (PCI), especially in patients with diabetes mellitus. Recently, some studies have shown that 5-ethynyl-2'-deoxyuridine (EdU) incorporation can serve as a novel alternative to the 5-bromo-2'-deoxyuridine (BrdU) antibody detection method for detection of DNA synthesis in regenerating avian cochlea, chick embryo and the adult nervous system. However, few studies have been performed to assess the suitability of EdU for detecting DNA synthesis in vascular neointima. Methods: The carotid artery balloon injury model was established in Goto-Kakizaki (GK) and Wistar rats. A Cell-Light (TM) EdU Kit was used to detect EdU-labeled cell nuclei of common carotid arteries at day 7 after catheter balloon injury. Different methods of injecting EdU were tested. The protein levels of proliferating cell nuclear antigen (PCNA) and p-Akt (Ser473), as well as the mRNA levels of PCNA were evaluated by Western blotting and quantitative real-time PCR (qRT-PCR), respectively. Immunohistochemical staining was also employed to visualize PCNA-positive cells. Results: At day 7 after catheter balloon injury, far more EdU-positive and PCNA-positive cells were observed in GK rats. When comparing groups that received different EdU doses, it was found that the percentage of EdU-positive cells at a dose of 100 mg/kg body weight was than at doses of 25 mg/kg and 50 mg/kg. The number of positive cells was significantly higher in the repeated injection group compared to the single injection group. Further, after balloon injury DNA synthesis in GK rats was more notable than in Wistar rats. Neointimal formation in GK rats was more obvious than in Wistar rats. The protein levels of PCNA and p-Akt (Ser473) and the mRNA levels of PCNA were increased in injured rats as compared to uninjured rats, and were significantly higher in GK rats than in Wistar rats. Conclusion: By intraperitoneal injections of EdU at a dose of 100 mg/kg three times, EdU incorporation can detect carotid arterial DNA synthesis caused by neointimal formation in GK rats and Wistar rats at day 7 after balloon injury by the EdU click reaction quickly and effectively. Moreover, more obvious DNA synthesis in the vascular neointima could be observed in GK rats than in Wistar rats.
Guo J S; Li D Y; Bai S R; Xu T D; Zhou Z M; Zhang Y B
Cardiovascular Diabetology
2012
2012-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1186/1475-2840-11-150" target="_blank" rel="noreferrer noopener">10.1186/1475-2840-11-150</a>
Chemopreventive Effect Of A Novel Oleanane Triterpenoid In A Chemically Induced Rodent Model Of Breast Cancer
amooranin; apoptosis; breast cancer; carcinogenesis; carcinoma cell-lines; cddo-methyl ester; cell; Chemoprevention; DMBA; growth arrest; mammary; mice; oleanane triterpenoid; Oncology; prevention; proliferation; rat; tumor-growth
Breast cancer represents one of the most frequently diagnosed cancers and predominant causes of death in women worldwide. The value of preventive therapy to limit the devastating impact of breast cancer is well established. Various plant triterpenoids and their synthetic analogs have shown significant promise as potent chemopreventive agents in breast cancer. The current study was initiated to investigate mechanism-based chemopreventive potential of a novel synthetic oleanane triterpenoid (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis, an experimental rodent tumor model that closely resembles human mammary cancer. Rats were orally administered with AMR-Me (0.8, 1.2 and 1.6 mg/kg) three times per week for 18 weeks. Following two weeks of AMR-Me treatment, mammary carcinogenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks following DMBA exposure), AMR-Me exhibited a striking inhibition of DMBA-induced mammary tumor incidence, total tumor burden, average tumor weight and reversed histopathological alterations without toxicity. AMR-Me dose-dependently suppressed abnormal cell proliferation, induced apoptosis, up-regulated pro-apoptotic protein Bax and down-regulated antiapoptotic protein Bcl-2 in mammary tumors. AMR-Me upregulated the transcriptional levels of Bax, Bad, caspase-3, caspase-7 and poly(ADP-ribose) polymerase and down-regulated Bcl-2. These results clearly demonstrate for the first time that novel triterpenoid AMR-Me exerts chemopreventive efficacy in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through mitochondrial pro-apoptotic mechanisms. AMR-Me could be developed as a chemopreventive drug to reduce the risk of human breast cancer that remains a devastating disease.
Bishayee A; Mandal A; Thoppil R J; Darvesh A S; Bhatia D
International Journal of Cancer
2013
2013-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/ijc.28108" target="_blank" rel="noreferrer noopener">10.1002/ijc.28108</a>
2.5d Constructs For Characterizing Phase Separated Polymer Blend Surface Morphology In Tissue Engineering Scaffolds
2; 3d; 5D scaffolds; cell-shape; differentiation; Engineering; L-lactide); Materials Science; mechanical-properties; poly(D; poly(e-caprolactone); polymer blends; porosity; proliferation; topography
Marszalek J E; Simon C G; Thodeti C; Adapala R K; Murthy A; Karim A
Journal of Biomedical Materials Research Part A
2013
2013-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/jbm.a.34439" target="_blank" rel="noreferrer noopener">10.1002/jbm.a.34439</a>
Differential Regulation Of The Cell Cycle By Alpha(1)-adrenergic Receptor Subtypes
adventitial fibroblasts; alpha(1b)-adrenergic receptor; arterial blood-pressure; dna-synthesis; Endocrinology & Metabolism; fibroblasts; gene-expression; kinase pathways; mitogen-activated protein; proliferation; rat-1; smooth-muscle-cells
Gonzalez-Cabrera P J; Shi T; Yun J; McCune D F; Rorabaugh B R; Perez D M
Endocrinology
2004
2004-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1210/en.2004-0728" target="_blank" rel="noreferrer noopener">10.1210/en.2004-0728</a>
Suppression Of The Invasive Capacity Of Human Breast Cancer Cells By Inhibition Of Urokinase Plasminogen Activator Via Amiloride And B428
angiogenesis; carcinoma; integrins; migration; prevention; prognostic marker; proliferation; pulmonary metastases; receptor; Surgery; tumor-cells
Evans D M; Sloan-Stakleff K
American Surgeon
2000
2000-05
Journal Article or Conference Abstract Publication
n/a
Chemopreventive Effect Of A Novel Oleanane Triterpenoid In A Chemically Induced Rodent Model Of Breast Cancer
amooranin; apoptosis; breast cancer; carcinogenesis; carcinoma cell-lines; cddo-methyl ester; cell; chemoprevention; DMBA; growth arrest; mammary; mice; Oleanane triterpenoid; Oncology; prevention; proliferation; rat; tumor-growth
Bishayee A; Mandal A; Thoppil R J; Darvesh A S; Bhatia D
International Journal of Cancer
2013
2013-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/ijc.28108" target="_blank" rel="noreferrer noopener">10.1002/ijc.28108</a>
Temperature regulates limb length in homeotherms by directly modulating cartilage growth
Allen's Rule; blood-flow; body size; bone; bone growth; bone tissue culture; cartilage biology; differentiation; endoplasmic-reticulum stress; environmental-temperature; fluorescent microsphere method; mouse; plate; proliferation; Science & Technology - Other Topics; tail-length; thermoregulation
Allen's Rule documents a century-old biological observation that strong positive correlations exist among latitude, ambient temperature, and limb length in mammals. Although genetic selection for thermoregulatory adaptation is frequently presumed to be the primary basis of this phenomenon, important but frequently overlooked research has shown that appendage outgrowth is also markedly influenced by environmental temperature. Alteration of limb blood flow via vasoconstriction/vasodilation is the current default hypothesis for this growth plasticity, but here we show that tissue perfusion does not fully account for differences in extremity elongation in mice. We show that peripheral tissue temperature closely reflects housing temperature in vivo, and we demonstrate that chondrocyte proliferation and extracellular matrix volume strongly correlate with tissue temperature in metatarsals cultured without vasculature in vitro. Taken together, these data suggest that vasomotor changes likely modulate extremity growth indirectly, via their effects on appendage temperature, rather than vascular nutrient delivery. When combined with classic evolutionary theory, especially genetic assimilation, these results provide a potentially comprehensive explanation of Allen's Rule, and may substantially impact our understanding of phenotypic variation in living and extinct mammals, including humans.
Serrat M A; King D; Lovejoy C O
Proceedings of the National Academy of Sciences of the United States of America
2008
2008-12
Journal Article
<a href="http://doi.org/10.1073/pnas.0803319105" target="_blank" rel="noreferrer noopener">10.1073/pnas.0803319105</a>
d2ome, Software for in Vivo Protein Turnover Analysis Using Heavy Water Labeling and LC-MS, Reveals Alterations of Hepatic Proteome Dynamics in a Mouse Model of NAFLD
40S ribosomal proteins; algorithm; amino-acids; Biochemistry & Molecular Biology; dna; in vivo protein turnover; isotopomer; Mass spectrometry; metabolic labeling; NAFLD; nonlinear least-squares modeling; peak detection and integration; proliferation; protein half-life; proteome dynamics; proteostasis; quantification; rates; respiratory-chain; steatosis; UPR
Metabolic labeling with heavy water followed by LC-MS is a high throughput approach to study proteostasis in vivo. Advances in mass spectrometry and sample processing have allowed consistent detection of thousands of proteins at multiple time points. However, freely available automated bioinformatics tools to analyze and extract protein decay rate constants are lacking. Here, we describe d2ome-a robust, automated software solution for in vivo protein turnover analysis. d2ome is highly scalable, uses innovative approaches to nonlinear fitting, implements Grubbs' outlier detection and removal, uses weighted-averaging of replicates, applies a data dependent elution time windowing, and uses mass accuracy in peak detection. Here, we discuss the application of d2ome in a comparative study of protein turnover in the livers of normal vs Western diet-fed LDLR-/- mice (mouse model of nonalcoholic fatty liver disease), which contained 256 LC-MS experiments. The study revealed reduced stability of 40S ribosomal protein subunits in the Western diet-fed mice.
Sadygov R G; Avva J; Rahman M; Lee K; Ilchenko S; Kasumov T; Borzou A
Journal of Proteome Research
2018
2018-11
Journal Article
<a href="http://doi.org/10.1021/acs.jproteorne.8b00417" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteorne.8b00417</a>
Growth plate formation and development in alligator and mouse metapodials: Evolutionary and functional implications
bone-development; bones; chondrocyte differentiation; Developmental Biology; Evolutionary Biology; indian-hedgehog; joint formation; long; morphogenesis; ossification; porpoise phocoena-phocoena; proliferation; skeleton formation; Zoology
Mammalian metapodials (metacarpals and metatarsals), unlike most long bones, form a single growth plate, and undergo longitudinal growth at only one end. The growth dynamics of non-mammalian tetrapod metapodials have not been systematically examined in order to determine if unidirectional growth is unique to mammals. Here we compare murine metapodial ossification in growth stages that parallel those of embryonic, juvenile and subadult American alligators (Alligator mississippiensis). Safranin O staining was used for qualitative histology, and chondrocyte differentiation and proliferation were assessed via immunohistochemistry for type X collagen and proliferative cell nuclear antigen (PCNA). We establish that growth plates form at both ends-of alligator metapodials and are maintained in the subadult. PCNA results show that alligators and mice share common patterns of chondrocyte proliferation during growth plate formation. In addition, while alligators and mice differ initially in the degree of organization and pace of chondrocyte differentiation, these parameters are largely similar in established growth plates. However, the replacement of cartilage by bone is highly irregular throughout growth in the alligator, in contrast to the more uniform process in the mouse. These results indicate that while alligators and mammals share common mechanisms of chondrocyte regulation, they differ substantially in their processes of ossification. Phylogenetic analysis indicates that the direct ossification of one epiphysis and reliance on a single growth plate is a derived character (synapomorphy) in therian mammals and likely indicates an adaptation for erect quadrupedal gait.
Reno P L; Horton W E; Elsey R M; Lovejoy C O
Journal of Experimental Zoology Part B-Molecular and Developmental Evolution
2007
2007-05
Journal Article
<a href="http://doi.org/10.1002/jez.b.21148" target="_blank" rel="noreferrer noopener">10.1002/jez.b.21148</a>
Automated, Spatio-Temporally Controlled Cell Microprinting With Polymeric Aqueous Biphasic System
aqueous two-phase system; Biotechnology & Applied Microbiology; cell printing; coculture; fabrication; geometries; liquid; mammalian-cells; mechanisms; proliferation; scaffolds; skeletal-muscle; tissue
Cell printing is a promising approach to create organized constructs for tissue engineering applications. We present an automated cell printing microtechnology based on the use of an aqueous two-phase system (ATPS) interfaced with a three-axis motorized system. Cells suspended in the denser aqueous dextran (DEX) phase are loaded into printing tips, which are placed onto the cartridge of the motorized system. Using a computer interface, tips are lowered in the vicinity of a biological surface maintained in the immersion, aqueous polyethylene glycol (PEG) phase to perform a horizontal motion, autonomously dispense their contents onto the surface, and retracted out of the PEG phase. The motorized ATPS technology allows precise spatial and temporal control of the printing process and supports printing fully viable cells. We conduct a systematic study and show that the resolution of ATPS-mediated cellular patterns depends on several factors including the dimensions of the printing tips, lateral speed of tips during horizontal motion, and the loaded volume of the DEX phase in the tips. The finest resolution is mu 300 mu m obtained with a tip diameter of 200 mm at a printing tip speed of 16.5 mm/s. Higher speeds result in unstable DEX patterns that break into drops due to capillary instability, and thus are avoided. We also test a number of printing substrates and find that in addition to a cell monolayer, decellularized matrices can serve as a substrate for cell printing with ATPS. Using the principles from the characterization studies, we create duplex prints of cells to demonstrate the potential of this approach for spatio-temporally controlled cell placement. The ATPS printing microtechnology will be a step forward toward developing well-organized, three-dimensional tissue constructs. (C) 2013 Wiley Periodicals, Inc.
Petrak D; Atefi E; Yin L Y; Chilian W; Tavana H
Biotechnology and Bioengineering
2014
2014-02
Journal Article
<a href="http://doi.org/10.1002/bit.25100" target="_blank" rel="noreferrer noopener">10.1002/bit.25100</a>
Endothelin-1 as a therapeutic target in autosomal dominant polycystic kidney disease
proliferation; hypertension; receptor; expression; Urology & Nephrology; growth-factor; renal damage; endothelin-1; excretion; polycystic kidney disease; chronic kidney disease; ADPKD; endothelin-1 antagonists; autosomal dominant; tolvaptan; urinary endothelin-1; water permeability
Aims: Endothelin-1 (ET-1) is associated with the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) via cyst progression. Elevated concentrations of ET-1 in ADPKD correlate with many phenotypic changes in the kidney such as renal cyst development, interstitial fibrosis, and glomerulosclerosis. In addition, an imbalance between renal ETA and ETB receptors possibly leads to more severe disease progression. The objective of this review is to determine whether evaluating the efficacy of these drugs in treatment of cystic kidney disease may be a worthwhile aim, as determined by results from animal and human models. Materials and methods: PubMed/Medline, Embase, and Google Scholar databases were searched using the key words "endothelin, endothelin-1 antagonists, and autosomal dominant polycystic kidney disease". All animal and human studies describing the effects of endothelin and endothelin-1 antagonists in ADPKD subjects were included in the review. Results: Urinary ET-1 concentrations could serve as a noninvasive surrogate biomarker for kidney ET-1 levels, as it is inversely associated with eGFR, independent of age, sex, and blood pressure. Elevated urinary excretion of ET-1 may be a biomarker for early renal injury. Antagonization of ET-1 may hopefully be a novel therapy for slowing progression of kidney damage in ADPKD. Conclusion: Based on the literature reviewed in this manuscript, it is proposed that further research evaluating the efficacy of endothelin antagonists in treatment of cystic kidney disease is warranted. More human studies need to be performed with larger sample sizes. Therefore, the recommendation for treatment is inconclusive at this time.
Raina R; Chauvin A; Vajapey R; Khare A; Krishnappa V
Clinical Nephrology
2019
2019-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.5414/cn109598" target="_blank" rel="noreferrer noopener">10.5414/cn109598</a>
Hyperglycemia enhances function and differentiation of adult rat cardiac fibroblasts.
*Cell Differentiation; Animals; Blood Glucose/metabolism; cardiac fibroblast; Cell Movement; Cell Proliferation; Cells; collagen; Collagen/metabolism; collagene; concentration elevee de glucose; Cultured; diabete; diabetes; fibroblaste cardiaque; Fibroblasts/*metabolism/pathology; Fibrosis; high glucose; Hyperglycemia/*metabolism/pathology; Male; migration; Myocardium/*metabolism/pathology; myofibroblast; myofibroblastes; proliferation; Rats; Signal Transduction; Sprague-Dawley
Diabetes is an independent risk factor for cardiovascular disease that can eventually cause cardiomyopathy and heart failure. Cardiac fibroblasts (CF) are the critical mediators of physiological and pathological cardiac remodeling; however, the effects of hyperglycemia on cardiac fibroblast function and differentiation is not well known. Here, we performed a comprehensive investigation on the effects of hyperglycemia on cardiac fibroblasts and show that hyperglycemia enhances cardiac fibroblast function and differentiation. We found that high glucose treatment increased collagen I, III, and VI gene expression in rat adult cardiac fibroblasts. Interestingly, hyperglycemia increased CF migration and proliferation that is augmented by collagen I and III. Surprisingly, we found that short term hyperglycemia transiently inhibited ERK1/2 activation but increased AKT phosphorylation. Finally, high glucose treatment increased spontaneous differentiation of cardiac fibroblasts to myofibroblasts with increasing passage compared with low glucose. Taken together, these findings suggest that hyperglycemia induces cardiac fibrosis by modulating collagen expression, migration, proliferation, and differentiation of cardiac fibroblasts.
Shamhart Patricia E; Luther Daniel J; Adapala Ravi K; Bryant Jennifer E; Petersen Kyle A; Meszaros J Gary; Thodeti Charles K
Canadian journal of physiology and pharmacology
2014
2014-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1139/cjpp-2013-0490" target="_blank" rel="noreferrer noopener">10.1139/cjpp-2013-0490</a>